This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of this project is to elucidate the role of posttranslational O-GlcNAc modification of protein Ser/Thr in the regulation of signal transduction events relevant to the complications associated with diabetes. We hypothesize that high glucose-induced elevation in O-GlcNAc glycosylation of cytoplasmic and/or nuclear proteins contributes to delayed healing of the periodontium and to the exaggerated response to infection observed in diabetic patients. Our first aim is to elucidate the mechanism by which O-GlcNAc modification of critical components of the insulin/IGF-1 receptor signaling pathways, IRS-1 and IRS-2, attenuates insulin signaling and to test the hypothesis that O-GlcNAc modification of these proteins attenuates IGF-1 receptor signaling. The second aim will test the hypothesis that IGF-1 signaling in periodontal ligament fibroblasts (PDLF) is attenuated by high glucose-induced O-GlcNAc modification. If this hypothesis is correct we anticipate that glucose-induced impairment of IGF-1 signaling may be alleviated by manipulation of the enzymes responsible for this modification, O-GlcNAcase and O-GlcNAc transferase. The third aim will determine whether the glucose-induced augmentation of LPS-stimulated secretion of MMP-1 from macrophages can be reduced by overexpression of the enzyme, O-GlcNAcase.